Source:http://www4.wiwiss.fu-berlin.de/dailymed/resource/drugs/263
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SEREVENT (Powder)
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SEREVENT DISKUS should be administered by the orally
inhaled route only (see Instructions for Using SEREVENT DISKUS in
the Medication Guide accompanying the product). The patient must not
exhale into the DISKUS and the DISKUS should only be activated and
used in a level, horizontal position.<br/>Asthma: Long-acting beta-adrenergic agonists,
such as salmeterol, the active ingredient in SEREVENT DISKUS, may
increase the risk of asthma-related death (see WARNINGS). Therefore,
when treating patients with asthma, SEREVENT DISKUS should only be
used as additional therapy for patients not adequately controlled
on other asthma-controller medications (e.g., low- to medium-dose
inhaled corticosteroids) or whose disease severity clearly warrants
initiation of treatment with 2 maintenance therapies, including SEREVENT
DISKUS. It is not indicated for patients whose asthma can be managed
by occasional use of inhaled, short-acting beta-agonists
or for patients whose asthma can be successfully managed by inhaled
corticosteroids or other controller medications along with occasional
use of inhaled, short-acting beta-agonists. For maintenance of bronchodilatation and prevention of
symptoms of asthma, including the symptoms of nocturnal asthma, the
usual dosage for adults and children 4 years of age and older
is 1 inhalation (50 mcg) twice daily (morning and evening, approximately
12 hours apart). If a previously effective dosage regimen fails
to provide the usual response, medical advice should be sought immediately
as this is often a sign of destabilization of asthma. Under these
circumstances, the therapeutic regimen should be reevaluated. If symptoms
arise in the period between doses, an inhaled, short-acting beta-agonist should be taken for immediate relief.<br/>Chronic Obstructive Pulmonary Disease: For maintenance treatment of bronchospasm associated
with COPD (including chronic bronchitis and emphysema), the usual
dosage for adults is 1 inhalation (50 mcg) twice daily (morning
and evening, approximately 12 hours apart). For both asthma and COPD, adverse effects are more likely to occur
with higher doses of salmeterol, and more frequent administration
or administration of a larger number of inhalations is not recommended. To gain full therapeutic benefit, SEREVENT DISKUS should
be administered twice daily (morning and evening) in the treatment
of reversible airway obstruction.<br/>Geriatric Use: Based on available data for SEREVENT DISKUS, no
dosage adjustment is recommended.<br/>Prevention of Exercise-Induced Bronchospasm: One inhalation of SEREVENT DISKUS at least 30 minutes
before exercise has been shown to protect patients against EIB. When
used intermittently as needed for prevention of EIB, this protection
may last up to 9 hours in adolescents and adults and up to 12 hours
in patients 4 to 11 years of age. Additional doses of SEREVENT should not be used for 12 hours after
the administration of this drug. Patients who are receiving SEREVENT
DISKUS twice daily should not use additional SEREVENT for prevention
of EIB. If regular, twice-daily dosing is not effective
in preventing EIB, other appropriate therapy for EIB should be considered.
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dailymed-instance:descripti... |
SEREVENT DISKUS (salmeterol xinafoate inhalation
powder) contains salmeterol xinafoate as the racemic form of the 1-hydroxy-2-naphthoic
acid salt of salmeterol. The active component of the formulation is
salmeterol base, a highly selective beta-adrenergic bronchodilator.
The chemical name of salmeterol xinafoate is 4-hydroxy-��-[[[6-(4-phenylbutoxy)hexyl]amino] methyl]-1,3-benzenedimethanol,
1-hydroxy-2-naphthalenecarboxylate. Salmeterol xinafoate has the following
chemical structure: Salmeterol
xinafoate is a white powder with a molecular weight of 603.8, and
the empirical formula is CHNO���CHO. It is freely soluble
in methanol; slightly soluble in ethanol, chloroform, and isopropanol;
and sparingly soluble in water. SEREVENT DISKUS
is a specially designed plastic inhalation delivery system containing
a double-foil blister strip of a powder formulation of salmeterol
xinafoate intended for oral inhalation only. The DISKUS, which is the delivery component, is an integral part of the drug
product. Each blister on the double-foil strip within the unit contains
50 mcg of salmeterol administered as the salmeterol xinafoate
salt in 12.5 mg of formulation containing lactose (which containsmilk proteins). After a blister containing medication is opened by
activating the DISKUS, the medication is dispersed into the airstream
created by the patient inhaling through the mouthpiece. Under standardized in vitro test conditions, SEREVENT
DISKUS delivers 47 mcg when tested at a flow rate of 60 L/min
for 2 seconds. In adult patients with obstructive lung disease
and severely compromised lung function (mean forced expiratory volume
in 1 second [FEV] 20% to 30% of predicted), mean
peak inspiratory flow (PIF) through a DISKUS was 82.4 L/min (range,
46.1 to 115.3 L/min). The actual amount
of drug delivered to the lung will depend on patient factors, such
as inspiratory flow profile.
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Mechanism of Action: Salmeterol is a long-acting beta-adrenergic
agonist. In vitro studies and in vivo pharmacologic studies demonstrate
that salmeterol is selective for beta-adrenoceptors compared
with isoproterenol, which has approximately equal agonist activity
on beta- and beta-adrenoceptors. In vitro
studies show salmeterol to be at least 50 times more selective for
beta-adrenoceptors than albuterol. Although beta-adrenoceptors are the predominant adrenergic receptors in bronchial
smooth muscle and beta-adrenoceptors are the predominant
receptors in the heart, there are also beta-adrenoceptors
in the human heart comprising 10% to 50% of the total beta-adrenoceptors.
The precise function of these receptors has not been established,
but they raise the possibility that even highly selective beta-agonists may have cardiac effects. The pharmacologic effects of beta-adrenoceptor agonist
drugs, including salmeterol, are at least in part attributable to
stimulation of intracellular adenyl cyclase, the enzyme that catalyzes
the conversion of adenosine triphosphate (ATP) to cyclic-3���,5���-adenosine
monophosphate (cyclic AMP). Increased cyclic AMP levels cause relaxation
of bronchial smooth muscle and inhibition of release of mediators
of immediate hypersensitivity from cells, especially from mast cells. In vitro tests show that salmeterol is a potent and long-lasting
inhibitor of the release of mast cell mediators, such as histamine,
leukotrienes, and prostaglandin D, from human lung. Salmeterol
inhibits histamine-induced plasma protein extravasation and inhibits
platelet-activating factor-induced eosinophil accumulation in the
lungs of guinea pigs when administered by the inhaled route. In humans,
single doses of salmeterol administered via inhalation aerosol attenuate
allergen-induced bronchial hyper-responsiveness.<br/>Pharmacokinetics: Salmeterol xinafoate, an ionic salt, dissociates
in solution so that the salmeterol and 1-hydroxy-2-naphthoic acid
(xinafoate) moieties are absorbed, distributed, metabolized, and eliminated
independently. Salmeterol acts locally in the lung; therefore, plasma
levels do not predict therapeutic effect.<br/>Absorption: Because of the small therapeutic dose, systemic
levels of salmeterol are low or undetectable after inhalation of recommended
doses (50 mcg of salmeterol inhalation powder twice daily). Following
chronic administration of an inhaled dose of 50 mcg of salmeterol
inhalation powder twice daily, salmeterol was detected in plasma within
5 to 45 minutes in 7 patients with asthma; plasma concentrations
were very low, with mean peak concentrations of 167 pg/mL at
20 minutes and no accumulation with repeated doses.<br/>Distribution: The percentage of salmeterol bound to human plasma
proteins averages 96% in vitro over the concentration range of 8 to
7,722 ng of salmeterol base per milliliter, much higher concentrations
than those achieved following therapeutic doses of salmeterol.<br/>Metabolism: Salmeterol base is extensively metabolized by hydroxylation,
with subsequent elimination predominantly in the feces. No significant
amount of unchanged salmeterol base has been detected in either urine
or feces. An in vitro study using human liver
microsomes showed that salmeterol is extensively metabolized to��-hydroxysalmeterol
(aliphatic oxidation) by cytochrome P450 3A4 (CYP3A4). Ketoconazole,
a strong inhibitor of CYP3A4, essentially completely inhibited the
formation of��-hydroxysalmeterol in vitro.<br/>Elimination: In 2 healthy subjects who received 1 mg of
radiolabeled salmeterol (as salmeterol xinafoate) orally, approximately
25% and 60% of the radiolabeled salmeterol was eliminated in urine
and feces, respectively, over a period of 7 days. The terminal
elimination half-life was about 5.5 hours (1 volunteer only). The xinafoate moiety has no apparent pharmacologic activity.
The xinafoate moiety is highly protein bound (>99%) and has a long
elimination half-life of 11 days.<br/>Special Populations: The pharmacokinetics of salmeterol base has not
been studied in elderly patients nor in patients with hepatic or renal
impairment. Since salmeterol is predominantly cleared by hepatic metabolism,
liver function impairment may lead to accumulation of salmeterol in
plasma. Therefore, patients with hepatic disease should be closely
monitored.<br/>Drug Interactions: Salmeterol is a substrate of CYP3A4.<br/>Pharmacodynamics: Inhaled salmeterol, like other beta-adrenergic agonist
drugs, can in some patients produce dose-related cardiovascular effects
and effects on blood glucose and/or serum potassium (see PRECAUTIONS:
General). The cardiovascular effects (heart rate, blood pressure)
associated with salmeterol inhalation aerosol occur with similar frequency,
and are of similar type and severity, as those noted following albuterol
administration. The effects of rising doses
of salmeterol and standard inhaled doses of albuterol were studied
in volunteers and in patients with asthma. Salmeterol doses up to
84 mcg administered as inhalation aerosol resulted in heart rate
increases of 3 to 16 beats/min, about the same as albuterol dosed
at 180 mcg by inhalation aerosol (4 to 10 beats/min). Adolescent
and adult patients receiving 50-mcg doses of salmeterol inhalation
powder (N = 60) underwent continuous electrocardiographic
monitoring during two 12-hour periods after the first dose and after
1 month of therapy, and no clinically significant dysrhythmias
were noted. Also, pediatric patients receiving 50-mcg doses of salmeterol
inhalation powder (N = 67) underwent continuous electrocardiographic
monitoring during two 12-hour periods after the first dose and after
3 months of therapy, and no clinically significant dysrhythmias
were noted. In 24-week clinical studies in
patients with chronic obstructive pulmonary disease (COPD), the incidence
of clinically significant abnormalities on the predose electrocardiograms
(ECGs) at Weeks 12 and 24 in patients who received salmeterol 50 mcg
was not different compared with placebo. No effect of treatment with salmeterol 50 mcg was observed on
pulse rate and systolic and diastolic blood pressure in a subset of
patients with COPD who underwent 12-hour serial vital sign measurements
after the first dose (N = 91) and after 12 weeks of
therapy (N = 74). Median changes from baseline in pulse
rate and systolic and diastolic blood pressure were similar for patients
receiving either salmeterol or placebo (see ADVERSE REACTIONS). Studies in laboratory animals (minipigs,
rodents, and dogs) have demonstrated the occurrence of cardiac arrhythmias
and sudden death (with histologic evidence of myocardial necrosis)
when beta-agonists and methylxanthines are administered concurrently.
The clinical significance of these findings is unknown.
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SEREVENT DISKUS is contraindicated in patients with
a history of hypersensitivity to salmeterol or any other component
of the drug product (see DESCRIPTION and ADVERSE REACTIONS: Observed
During Clinical Practice: Non-Site Specific).
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dailymed-instance:supply |
SEREVENT DISKUS is supplied as a disposable teal
green unit containing 60 blisters. The drug product is packaged
within a teal green, plastic-coated, moisture-protective foil pouch
(NDC 0173-0521-00). SEREVENT DISKUS is also supplied in an institutional pack of 1 disposable teal green
unit containing 28 blisters. The drug product is packaged within
a teal green, plastic-coated, moisture-protective foil pouch (NDC
0173-0520-00). Store
at controlled room temperature (see USP), 20��to 25��C (68��to 77��F) in a dry place away from direct heat or sunlight. Keep
out of reach of children. SEREVENT DISKUS should be discarded 6 weeks
after removal from the moisture-protective foil pouch or after all
blisters have been used (when the dose indicator reads������),
whichever comes first. The DISKUS is not reusable. Do not attempt
to take the DISKUS apart. GlaxoSmithKline Research Triangle Park, NC 27709 ��2008, GlaxoSmithKline. All rights reserved. March 2008SRD:3PI
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WARNING: Long-acting beta-adrenergic agonists,
such as salmeterol, the active ingredient in SEREVENT DISKUS, may
increase the risk of asthma-related death. Therefore, when treating
patients with asthma, SEREVENT DISKUS should only be used as additional
therapy for patients not adequately controlled on other asthma-controller
medications (e.g., low- to medium-dose inhaled corticosteroids) or
whose disease severity clearly warrants initiation of treatment with
2 maintenance therapies, including SEREVENT DISKUS. Data from a large
placebo-controlled US study that compared the safety of salmeterol
(SEREVENTInhalation Aerosol) or placebo added to
usual asthma therapy showed an increase in asthma-related deaths in
patients receiving salmeterol (13 deaths out of 13,176 patients treated
for 28 weeks on salmeterol versus 3 deaths out of 13,179 patients
on placebo) (see WARNINGS and CLINICAL TRIALS: Asthma: Salmeterol Multi-center Asthma Research Trial).
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General:<br/>Cardiovascular Effects: No effect on the cardiovascular system is usually
seen after the administration of inhaled salmeterol at recommended
doses, but the cardiovascular and central nervous system effects seen
with all sympathomimetic drugs (e.g., increased blood pressure, heart
rate, excitement) can occur after use of salmeterol and may require
discontinuation of SEREVENT DISKUS. SEREVENT DISKUS, like all sympathomimetic
amines, should be used with caution in patients with cardiovascular
disorders, especially coronary insufficiency, cardiac arrhythmias,
and hypertension; in patients with convulsive disorders or thyrotoxicosis;
and in patients who are unusually responsive to sympathomimetic amines. As has been described with other beta-adrenergic agonist
bronchodilators, clinically significant changes in systolic and/or
diastolic blood pressure, pulse rate, and ECGs have been seen infrequently
in individual patients in controlled clinical studies with salmeterol.<br/>Metabolic Effects: Doses of the related beta-adrenoceptor
agonist albuterol, when administered intravenously, have been reported
to aggravate preexisting diabetes mellitus and ketoacidosis. Beta-adrenergic
agonist medications may produce significant hypokalemia in some patients,
possibly through intracellular shunting, which has the potential to
produce adverse cardiovascular effects. The decrease in serum potassium
is usually transient, not requiring supplementation. Clinically significant changes in blood glucose and/or serum potassium
were seen rarely during clinical studies with long-term administration
of SEREVENT DISKUS at recommended doses.<br/>Information for Patients: Patients should be instructed
to read the accompanying Medication Guide with each new prescription
and refill. The complete text of the Medication Guide is reprinted
at the end of this document. Patients
being treated with SEREVENT DISKUS should receive
the following information and instructions. This information is intended
to aid them in the safe and effective use of this medication. It is
not a disclosure of all possible adverse or intended effects. It is important that patients understand how to use the DISKUS appropriately and how to use SEREVENT DISKUS in
relation to other asthma or COPD medications they are taking. Patients
should be given the following information:<br/>Drug Interactions:<br/>Inhibitors of Cytochrome
P450 3A4:: In a drug interaction study in 20 healthy subjects,
coadministration of salmeterol (50 mcg twice daily) and ketoconazole
(400 mg once daily) for 7 days resulted in greater systemic
exposure to salmeterol (AUC increased 16-fold and Cincreased
1.4-fold). Three (3) subjects were withdrawn due to beta-agonist side effects (2 with prolonged QTc and 1 with palpitations
and sinus tachycardia). Although there was no statistical effect on
the mean QTc, coadministration of salmeterol and ketoconazole was
associated with more frequent increases in QTc duration compared with
salmeterol and placebo administration. Due to the potential increased
risk of cardiovascular adverse events, theconcomitant use of salmeterol
with strong CYP3A4 inhibitors (e.g., ketoconazole, ritonavir, atazanavir,
clarithromycin, indinavir, itraconazole, nefazodone, nelfinavir, saquinavir,
telithromycin) is not recommended.<br/>Short-Acting Beta-Agonists: In two 12-week, repetitive-dose adolescent and adult
clinical trials in patients with asthma (N = 149), the mean
daily need for additional beta-agonist in patients using
SEREVENT DISKUS was approximately 1��inhalations/day. Twenty-six
percent (26%) of the patients in these trials used between 8 and 24 inhalations
of short-acting beta-agonist per day on 1 or more occasions. Nine
percent (9%) of the patients in these trials averaged over 4 inhalations/day
over the course of the 12-week trials. No increase in frequency of
cardiovascular events was observedamong the 3 patients who averaged
8 to 11 inhalations/day; however, the safety of concomitant use of
more than 8 inhalations/day of short-acting beta-agonist
with SEREVENT DISKUS has not been established. In 29 patients
who experienced worsening of asthma while receiving SEREVENT DISKUS
during these trials, albuterol therapy administered via either nebulizer
or inhalation aerosol (1 dose in most cases) led to improvement
in FEVand no increase in occurrence of cardiovascular
adverse events. In 2 clinical trials in patients
with COPD, the mean daily need for additional beta-agonist
for patients using SEREVENT DISKUS was approximately 4 inhalations/day.
Twenty-four percent (24%) of the patients using SEREVENT DISKUS in
these trials averaged 6 or more inhalations of albuterol per day over
the course of the 24-week trials. No increase in frequency of cardiovascular
events was observed among patients who averaged 6 or more inhalations
per day.<br/>Monoamine Oxidase Inhibitors
and Tricyclic Antidepressants: Salmeterol should be administered with extreme caution
to patients being treated with monoamine oxidase inhibitors or tricyclic
antidepressants, or within 2 weeks of discontinuation of such agents,
because the action of salmeterol on the vascular system may be potentiated
by these agents.<br/>Corticosteroids and Cromoglycate: In clinical trials, inhaled corticosteroids and/or
inhaled cromolyn sodium did not alter the safety profile of salmeterol
when administered concurrently.<br/>Methylxanthines: The concurrent use of intravenously or orally administered
methylxanthines (e.g., aminophylline, theophylline) by patients receiving
salmeterol has not been completely evaluated. In 1 clinical asthma
trial, 87 patients receiving SEREVENT Inhalation
Aerosol 42 mcg twice daily concurrently with a theophylline product
had adverse event rates similar to those in 71 patients receiving SEREVENT Inhalation Aerosol without theophylline. Resting
heart rates were slightly higher in the patients on theophylline but
were little affected by therapy with SEREVENT Inhalation
Aerosol. In 2 clinical trials in patients
with COPD, 39 subjects receiving SEREVENT DISKUS concurrently with
a theophylline product had adverse event rates similar to those in
302 patients receiving SEREVENT DISKUS without theophylline. Based
on the available data, the concomitant administration of methylxanthines
with SEREVENT DISKUS did not alter the observed adverse event profile.<br/>Beta-Adrenergic Receptor
Blocking Agents: Beta-blockers not only block the pulmonary effect
of beta-agonists, such as SEREVENT DISKUS, but may also produce severe
bronchospasm in patients with asthma or COPD. Therefore, patients
with asthma or COPD should not normally be treated with beta-blockers.
However, under certain circumstances, e.g., as prophylaxis after myocardial
infarction, there may be no acceptable alternatives to the use of
beta-adrenergic blocking agents in patients with asthma or COPD. In
this setting, cardioselective beta-blockers could be considered, although
they should be administered with caution.<br/>Diuretics: The ECG changes and/or hypokalemia that may result
from the administration of nonpotassium-sparing diuretics (such as
loop or thiazide diuretics) can be acutely worsened by beta-agonists,
especially when the recommended dose of the beta-agonist is exceeded.
Although the clinical significance of these effects is not known,
caution is advised in the coadministration of beta-agonists with nonpotassium-sparing
diuretics.<br/>Carcinogenesis, Mutagenesis, Impairment
of Fertility: In an 18-month oral carcinogenicity study in CD-mice,
salmeterol xinafoate caused a dose-related increase in the incidence
of smooth muscle hyperplasia, cystic glandular hyperplasia, leiomyomas
of the uterus, and ovarian cysts at doses of 1.4 mg/kg and above
(approximately 20 times the maximum recommended daily inhalation dose
in adults and children based on comparison of the area under the plasma
concentration versus time curves [AUCs]). The incidence of leiomyosarcomas
was not statistically significant. No tumors were seen at 0.2 mg/kg
(approximately 3 times the maximum recommended daily inhalation
doses in adults and children based on comparison of the AUCs). In a 24-month oral and inhalation carcinogenicity study
in Sprague Dawley rats, salmeterol caused a dose-related increase
in the incidence of mesovarian leiomyomas and ovarian cysts at doses
of 0.68 mg/kg and above (approximately 55 times the maximum recommended
daily inhalation dose in adults and approximately 25 times the maximum
recommended daily inhalation dose in children on a mg/mbasis). No tumors were seen at 0.21 mg/kg (approximately 15
times the maximum recommended daily inhalation dose in adults and
approximately 8 times the maximum recommended daily inhalation dose
in children on a mg/mbasis). These findings in rodents
are similar to those reported previously for other beta-adrenergic
agonist drugs. The relevance of these findings to human use is unknown. Salmeterol produced no detectable or reproducible increases
in microbial and mammalian gene mutation in vitro. No clastogenic
activity occurred in vitro in human lymphocytes or in vivo in a rat
micronucleus test. No effects on fertility were identified in male
and female rats treated with salmeterol at oral doses up to 2 mg/kg
(approximately 160 times the maximum recommended daily inhalation
dose in adults on a mg/mbasis).<br/>Pregnancy:<br/>Teratogenic Effects: Pregnancy Category C. No teratogenic effects occurred
in rats at oral doses up to 2 mg/kg (approximately 160 times
the maximum recommended daily inhalation dose in adults on a mg/mbasis). In pregnant Dutch rabbits administered oral doses
of 1 mg/kg and above (approximately 50 times the maximum recommended
daily inhalation dose in adults based on comparison of the AUCs),
salmeterol exhibited fetal toxic effects characteristically resulting
from beta-adrenoceptor stimulation. These included precocious eyelid
openings, cleft palate, sternebral fusion, limb and paw flexures,
and delayed ossification of the frontal cranial bones. No significant
effects occurred at an oral dose of 0.6 mg/kg (approximately
20 times the maximum recommended daily inhalation dose in adults based
on comparison of the AUCs). New Zealand White
rabbits were less sensitive since only delayed ossification of the
frontal bones was seen at an oral dose of 10 mg/kg (approximately
1,600 times the maximum recommended daily inhalation dose in adults
on a mg/mbasis). Extensive use of other beta-agonists
has provided no evidence that these class effects in animals are relevant
to their use in humans. There are no adequate and well-controlled
studies with SEREVENT DISKUS in pregnant women. SEREVENT DISKUS should
be used during pregnancy only if the potential benefit justifies the
potential risk to the fetus. Salmeterol xinafoate
crossed the placenta following oral administration of 10 mg/kg
to mice and rats (approximately 410 and 810 times, respectively, the
maximum recommended daily inhalation dose in adults on a mg/mbasis).<br/>Use in Labor and Delivery: There are no well-controlled human studies that
have investigated effects of salmeterol on preterm labor or labor
at term. Because of the potential for beta-agonist interference with
uterine contractility, use of SEREVENT DISKUS during labor should
be restricted to those patients in whom the benefits clearly outweigh
the risks.<br/>Nursing Mothers: Plasma levels of salmeterol after inhaled therapeutic
doses are very low. In rats, salmeterol xinafoate is excreted in the
milk. However, since there are no data from controlled trials on the
use of salmeterol by nursing mothers, a decision should be made whether
to discontinue nursing or to discontinue SEREVENT DISKUS, taking into
account the importance of SEREVENT DISKUS to the mother. Caution should
be exercised when SEREVENT DISKUS is administered to a nursing woman.<br/>Pediatric Use: The safety and efficacy of SEREVENT DISKUS has been
evaluated in over 2,500 patients aged 4 to 11 years with asthma,
346 of whom were administered SEREVENT DISKUS for 1 year. Based
on available data, no adjustment of dosage of SEREVENT DISKUS in pediatric
patients is warranted for either asthma or EIB (see DOSAGE AND ADMINISTRATION). In 2 randomized, double-blind, controlled clinical trials
of 12 weeks' duration, SEREVENT DISKUS 50 mcg was administered
to 211 pediatric patients with asthma who did and who did not receive
concurrent inhaled corticosteroids. The efficacy of SEREVENT DISKUS
was demonstrated over the 12-week treatment period with respect to
PEF and FEV. SEREVENT DISKUS was effective in demographic
subgroups (gender and age) of the population. SEREVENT DISKUS was
effective when coadministered with other inhaled asthma medications,
such as short-acting bronchodilators and inhaled corticosteroids.
SEREVENT DISKUS was well tolerated in the pediatric population, and
there were no safety issues identified specific to the administration
of SEREVENT DISKUS to pediatric patients. In
2 randomized studies in children 4 to 11 years old with asthma
and EIB, a single 50-mcg dose of SEREVENT DISKUS prevented EIB when
dosed 30 minutes prior to exercise, with protection lasting up
to 11.5 hours in repeat testing following this single dose in
many patients.<br/>Geriatric Use: Of the total number of adolescent and adult patients
with asthma who received SEREVENT DISKUS in chronic dosing clinical
trials, 209 were 65 years of age and older. Of the total number of
patients with COPD who received SEREVENT DISKUS in chronic dosing
clinical trials, 167 were 65 years of age or older and 45 were 75
years of age or older. No apparent differences in the safety of SEREVENT DISKUS were observed when geriatric patients were
compared with younger patients in clinical trials. As with other beta-agonists, however, special caution should be observed when
using SEREVENT DISKUS in geriatric patients who
have concomitant cardiovascular disease that could be adversely affected
by this class of drug. Data from the trials in patients with COPD
suggested a greater effect on FEVof SEREVENT DISKUS in
the<65 years age-group, as compared with the���65 years
age-group. However, based on available data, no adjustment of dosage
of SEREVENT DISKUS in geriatric patients is warranted.
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dailymed-instance:overdosag... |
The expected signs and symptoms with overdosage
of SEREVENT DISKUS are those of excessive beta-adrenergic stimulation
and/or occurrence or exaggeration of any of the signs and symptoms
listed under ADVERSE REACTIONS, e.g., seizures, angina, hypertension
or hypotension, tachycardia with rates up to 200 beats/min, arrhythmias,
nervousness, headache, tremor, muscle cramps, dry mouth, palpitation,
nausea, dizziness, fatigue, malaise, and insomnia. Overdosage with
SEREVENT DISKUS may be expected to result in exaggeration of the pharmacologic
adverse effects associated with beta-adrenoceptor agonists, including
tachycardia and/or arrhythmia, tremor, headache, and muscle cramps.
Overdosage with SEREVENT DISKUS can lead to clinically significant
prolongation of the QTc interval, which can produce ventricular arrhythmias.
Other signs of overdosage may include hypokalemia and hyperglycemia. As with all sympathomimetic medications, cardiac arrest
and even death may be associated with abuse of SEREVENT DISKUS. Treatment consists of discontinuation of SEREVENT DISKUS
together with appropriate symptomatic therapy. The judicious use of
a cardioselective beta-receptor blocker may be considered, bearing
in mind that such medication can produce bronchospasm. There is insufficient
evidence to determine if dialysis is beneficial for overdosage of
SEREVENT DISKUS. Cardiac monitoring is recommended in cases of overdosage. No deaths were seen in rats at an inhalation dose of
2.9 mg/kg (approximately 240 times the maximum recommended daily
inhalation dose in adults and approximately 110 times the maximum
recommended daily inhalation dose in children on a mg/mbasis) and in dogs at an inhalation dose of 0.7 mg/kg (approximately
190 times the maximum recommended daily inhalation dose in adults
and approximately 90 times the maximum recommended daily inhalation
dose in children on a mg/mbasis). By the oral route,
no deaths occurred in mice at 150 mg/kg (approximately 6,100
times the maximum recommended daily inhalation dose in adults and
approximately 2,900 times the maximum recommended daily inhalation
dose in children on a mg/mbasis) and in rats at 1,000 mg/kg
(approximately 81,000 times the maximum recommended daily inhalation
dose in adults and approximately 38,000 times the maximum recommended
daily inhalation dose in children on a mg/mbasis).
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salmeterol xinafoate
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SEREVENT (Powder)
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dailymed-instance:adverseRe... |
Data from a large, 28-week,
placebo-controlled US study that compared the safety of salmeterol
(SEREVENT Inhalation Aerosol) or placebo added to usual asthma therapy
showed an increase in asthma-related deaths in patients receiving
salmeterol (see WARNINGS and CLINICAL TRIALS: Asthma: Salmeterol Multi-center Asthma Research Trial).<br/>Asthma: Two multicenter, 12-week, controlled studies have
evaluated twice-daily doses of SEREVENT DISKUS in patients 12 years
of age and older with asthma. Table 4 reports the incidence of adverse
events in these 2 studies. Table 4 includes all events (whether considered
drug-related or nondrug-related by the investigator) that occurred
at a rate of 3% or greater in the group receiving SEREVENT DISKUS
and were more common than in the placebo group. Pharyngitis, sinusitis, upper respiratory tract infection, and cough
occurred at���3% but were more common in the placebo group.
However, throat irritation has been described at rates exceeding that
of placebo in other controlled clinical trials. Other adverse events that occurred in the group receiving SEREVENT
DISKUS in these studies with an incidence of 1% to 3% and that occurred
at a greater incidence than with placebo were:<br/>Ear, Nose, and Throat: Sinus headache.<br/>Gastrointestinal: Nausea.<br/>Mouth and Teeth: Oral mucosal abnormality.<br/>Musculoskeletal: Pain in joint.<br/>Neurological: Sleep disturbance, paresthesia.<br/>Skin: Contact dermatitis, eczema.<br/>Miscellaneous: Localized aches and pains, pyrexia of unknown origin. Two multicenter, 12-week, controlled studies have evaluated
twice-daily doses of SEREVENT DISKUS in patients aged 4 to 11 years
with asthma. Table 5 includes all events (whether considered drug-related
or nondrug-related by the investigator) that occurred at a rate of
3% or greater in the group receiving SEREVENT DISKUS and were more
common than in the placebo group. The following events were reported at an incidence
of 1% to 2% (3 to 4 patients) in the salmeterol group and with a higher
incidence than in the albuterol and placebo groups: gastrointestinal
signs and symptoms, lower respiratory signs and symptoms, photodermatitis,
and arthralgia and articular rheumatism. In
clinical trials evaluating concurrent therapy of salmeterol with inhaled
corticosteroids, adverse events were consistent with those previously
reported for salmeterol, or with events that would be expected with
the use of inhaled corticosteroids.<br/>Chronic Obstructive Pulmonary Disease: Two multicenter, 24-week, controlled studies have
evaluated twice-daily doses of SEREVENT DISKUS in patients with COPD.
For presentation (Table 6), the placebo data from a third trial, identical
in design, patient entrance criteria, and overall conduct but comparing
fluticasone propionate with placebo, were integrated with the placebo
data from these 2 studies (total N = 341 for salmeterol
and 576 for placebo). Other events occurring in the group receiving
SEREVENT DISKUS that occurred at a frequency of 1% to<3% and were
more common than in the placebo group were as follows:<br/>Endocrine and Metabolic: Hyperglycemia.<br/>Eye: Keratitis and conjunctivitis.<br/>Gastrointestinal: Candidiasis mouth/throat, dyspeptic symptoms, hyposalivation,
dental discomfort and pain, gastrointestinal infections.<br/>Lower Respiratory: Lower respiratory signs and symptoms.<br/>Musculoskeletal: Arthralgia and articular rheumatism; muscle pain;
bone and skeletal pain; musculoskeletal inflammation; muscle stiffness,
tightness, and rigidity.<br/>Neurology: Migraines.<br/>Non-Site Specific: Pain, edema and swelling.<br/>Psychiatry: Anxiety.<br/>Skin: Skin rashes. Adverse reactions
to salmeterol are similar in nature to those seen with other selective
beta-adrenoceptor agonists, i.e., tachycardia; palpitations;
immediate hypersensitivity reactions, including urticaria, angioedema,
rash, bronchospasm (see WARNINGS); headache; tremor; nervousness;
and paradoxical bronchospasm (see WARNINGS).<br/>Observed During Clinical Practice: In addition to adverse events reported from clinical
trials, the following events have been identified during postapproval
use of salmeterol. Because they are reported voluntarily from a population
of unknown size, estimates of frequency cannot be made. These events
have been chosen for inclusion due to either their seriousness, frequency
of reporting, or causal connection to salmeterol or a combination
of these factors. In extensive US and worldwide
postmarketing experience with salmeterol, serious exacerbations of
asthma, including some that have been fatal, have been reported. In
most cases, these have occurred in patients with severe asthma and/or
in some patients in whom asthma has been acutely deteriorating (see
WARNINGS), but they have also occurred in a few patients with less
severe asthma. It was not possible from these reports to determine
whether salmeterol contributed to these events.<br/>Respiratory: Reports of upper airway symptoms of laryngeal spasm,
irritation, or swelling such as stridor or choking; oropharyngeal
irritation.<br/>Cardiovascular: Arrhythmias (including atrial fibrillation, supraventricular
tachycardia, extrasystoles), and anaphylaxis.<br/>Non-Site Specific: Very rare anaphylactic reaction in patients with
severe milk protein allergy.
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See PRECAUTIONS: Information
for Patients and the Medication Guide accompanying the product. The following additional
WARNINGS about SEREVENT DISKUS should be noted. 1. SEREVENT DISKUS should
not be used as a treatment for acutely deteriorating asthma. SEREVENT DISKUS is intended for the maintenance treatment of asthma
(see INDICATIONS AND USAGE) and should not be introduced in acutely
deteriorating asthma, which is a potentially life-threatening condition.
There are no data demonstrating that SEREVENT DISKUS provides greater
efficacy than or additional efficacy to inhaled, short-acting beta-agonists in patients with worsening asthma. Serious acute
respiratory events, including fatalities, have been reported both
in the United States and worldwide in patients receiving SEREVENT. In most cases, these have occurred in patients
with severe asthma (e.g., patients with a history of corticosteroid
dependence, low pulmonary function, intubation, mechanical ventilation,
frequent hospitalizations, or previous life-threatening acute asthma
exacerbations) and/or in some patients in whom asthma has been acutely
deteriorating (e.g., unresponsive to usual medications; increasing
need for inhaled, short-acting beta-agonists; increasing
need for systemic corticosteroids; significant increase in symptoms;
recent emergency room visits; sudden or progressive deterioration
in pulmonary function). However, they have occurred in a few patients
with less severe asthma as well. It was not possible from these reports
to determine whether SEREVENT contributed to these
events. 2. SEREVENT
DISKUS should not be used to treat acute symptoms. An inhaled,
short-acting beta-agonist, not SEREVENT DISKUS, should
be used to relieve acute asthma or COPD symptoms. When prescribing
SEREVENT DISKUS, the physician must also provide the patient with
an inhaled, short-acting beta-agonist (e.g., albuterol)
for treatment of symptoms that occur acutely, despite regular twice-daily
(morning and evening) use of SEREVENT DISKUS. When beginning treatment with SEREVENT DISKUS, patients who have
been taking inhaled, short-acting beta-agonists on a regular
basis (e.g., 4 times a day) should be instructed to discontinue the
regular use of these drugs and use them only for symptomatic relief
of acute asthma or COPD symptoms (see PRECAUTIONS: Information for
Patients). 3. Increasing use of inhaled, short-acting beta-agonists
is a marker of deteriorating asthma or COPD. The physician
and patient should be alert to such changes. The patient's
condition may deteriorate acutely over a period of hours or chronically
over several days or longer. If the patient's inhaled, short-acting
beta-agonist becomes less effective, the patient needs
more inhalations than usual, or the patient develops a significant
decrease in PEF or lung function, these may be markers of destabilization
of their disease. In this setting, the patient requires immediate
reevaluation with reassessment of the treatment regimen, giving special
consideration to the possible need for corticosteroids. If the patient
uses 4 or more inhalations per day of an inhaled, short-acting beta-agonist for 2 or more consecutive days, or if more than 1
canister (200 inhalations per canister) of inhaled, short-acting
beta-agonist is used in an 8-week period in conjunction
with SEREVENT DISKUS, then the patient should consult the physician
for reevaluation. Increasing the daily dosage
of SEREVENT DISKUS in this situation is not appropriate. SEREVENT
DISKUS should not be used more frequently than twice daily (morning
and evening) at the recommended dose of 1 inhalation. 4. SEREVENT DISKUS should
not be used in conjunction with an inhaled, long-acting beta-agonist. SEREVENT DISKUS should not be used with other
medications containing long-acting beta-agonists. 5. SEREVENT DISKUS is not
a substitute for oral or inhaled corticosteroids. There
are no data demonstrating that SEREVENT DISKUS has a clinical anti-inflammatory
effect and could be expected to take the place of corticosteroids.
When initiating SEREVENT DISKUS in patients receiving oral or inhaled
corticosteroids for treatment of asthma, patients should be continued
on a suitable dose of corticosteroids to maintain clinical stabilityeven if they feel better as a result of initiating SEREVENT DISKUS.
Any change in corticosteroid dosage should be made ONLY after clinical
evaluation (see PRECAUTIONS: Information for Patients). 6. The recommended dosage
should not be exceeded. As with other inhaled beta-adrenergic drugs, SEREVENT DISKUS should not be used more often
or at higher doses than recommended. Fatalities have been reported
in association with excessive use of inhaled sympathomimetic drugs.
Large doses of inhaled or oral salmeterol (12 to 20 times the recommended
dose) have been associated with clinically significant prolongation
of the QTc interval, which has the potential for producing ventriculararrhythmias. 7. Paradoxical bronchospasm. As with other inhaled asthma
and COPD medications, SEREVENT DISKUS can produce paradoxical bronchospasm,
which may be life threatening. If paradoxical bronchospasm occurs
following dosing with SEREVENT DISKUS, it should be treated immediately
with a short-acting, inhaled bronchodilator; SEREVENT DISKUS should
be discontinued immediately; and alternative therapy should be instituted. 8. Immediate hypersensitivity
reactions. Immediate hypersensitivity reactions may occur
after administration of SEREVENT DISKUS, as demonstrated by cases
of urticaria, angioedema, rash, and bronchospasm. 9. Upper airway symptoms. Symptoms of laryngeal spasm, irritation, or swelling, such as stridor
and choking, have been reported in patients receiving SEREVENT DISKUS. 10. Cardiovascular disorders. SEREVENT DISKUS, like all sympathomimetic amines, should be used
with caution in patients with cardiovascular disorders, especially
coronary insufficiency, cardiac arrhythmias, and hypertension. SEREVENT
DISKUS, like all other beta-adrenergic agonists, can produce a clinically
significant cardiovascular effect in some patients as measured by
pulse rate, blood pressure, and/or symptoms. Although such effects
are uncommon after administration of SEREVENT DISKUS at recommended
doses, if they occur, the drug may need to be discontinued. In addition,
beta-agonists have been reported to produce ECG changes, such as flattening
of the T wave, prolongation of the QTc interval, and ST segment
depression. The clinical significance of these findings is unknown. 11. Potential drug interactions. Because of the potential for drug interactions and the potential
for increased risk of cardiovascular adverse events, the concomitant
use of SEREVENT DISKUS with strong CYP 3A4 inhibitors (e.g., ketoconazole,
ritonavir, atazanavir, clarithromycin, indinavir, itraconazole, nefazodone,
nelfinavir, saquinavir, telithromycin) is not recommended (see CLINICAL
PHARMACOLOGY: Pharmacokinetics: Drug
Interactions).
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Asthma: SEREVENT DISKUS is indicated for long-term, twice-daily
(morning and evening) administration in the maintenance treatment
of asthma and in the prevention of bronchospasm in patients 4 years
of age and older with reversible obstructive airway disease, including
patients with symptoms of nocturnal asthma. Long-acting beta-adrenergic agonists, such as salmeterol,
the active ingredient in SEREVENT DISKUS, may increase
the risk of asthma-related death (see WARNINGS).
Therefore, when treating patients with asthma, SEREVENT DISKUS should
only be used as additional therapy for patients not adequately controlled
on other asthma-controller medications (e.g., low- to medium-dose
inhaled corticosteroids) or whose disease severity clearly warrants
initiation of treatment with 2 maintenance therapies, including SEREVENT
DISKUS. It is not indicated for patients whose asthma can be managed
by occasional use of inhaled, short-acting beta-agonists
or for patients whose asthma can be successfully managed by inhaled
corticosteroids or other controller medications along with occasional
use of inhaled, short-acting beta-agonists. SEREVENT DISKUS is also indicated for prevention of exercise-induced
bronchospasm in patients 4 years of age and older.<br/>Chronic Obstructive Pulmonary Disease: SEREVENT DISKUS is indicated for the long-term,
twice-daily (morning and evening) administration in the maintenance
treatment of bronchospasm associated with COPD (including emphysema
and chronic bronchitis).
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SEREVENT
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